As well as containing antigenic substances, vaccines contain substances such as diluents, excipients, preservatives, stabilisers and buffers. Typically, vaccines also contain adjuvants, i.e., a substance which improves the immune response raised in response to the vaccine antigen.
The adjuvants traditionally used in human vaccines have been aluminium salts such as aluminium hydroxide and aluminium phosphate. Many other experimental adjuvants are known and these are reviewed in, for instance, reference 1. Adsorption to aluminium salts remains, however, the most common vaccine adjuvant formulation.
Although their use is widespread, aluminium salts may not always be compatible with particular antigens. It has been suggested, for instance, that aluminium hydroxide may not be suitable for use in multivalent vaccines including hepatitis B virus surface antigen [2] or for use with the capsular polysaccharide from Haemophilus influenzae [3]. It has also been suggested that different antigens within the same vaccine formulation should be adsorbed to different aluminium salts [4] for compatibility reasons.
As well as antigen compatibility, it is necessary to consider vaccine stability when using aluminium salts. For instance, their capacity for protein adsorption has been shown to drop over time at room temperature [5] and in response to autoclaving [6]. Alum salts may also cause difficulties in freeze drying [7]. Furthermore, it has been found that aluminium hydroxide can hydrolyse saccharide antigens [8], even at low temperatures and when the antigen is conjugated to a carrier protein, thus leading to reduced efficacy.
In general, these issues only arise when attention moves to formulating an antigen for clinical use and may not be appreciated during initial research and development of the antigen itself.
It is an object of the invention to provide improvements in the stability of vaccines which include aluminium salts and, in particular, improvements in pH stability (buffering) and adjuvant adsorption at various temperatures and/or improvements in antigen stability (e.g., reduction in hydrolysis).